tbuckley/cabot-search huggingface dataset:
A blood test for multiple cancers: game changer or overhyped?
Authors: Jacqui Wise
Journal: BMJ (2022)

<b>Background:</b> Research of drug sensibility testing (DST) to new drugs – bedaquiline (BDQ), linezolid (LNZ) and moxifloxacin (Mfx), is necessary step in providing complete treatment MDR/XDR TB cases. <b>Aims and objectives:</b> To determine medico-social features - risk factors of drug resistance development to Mfx and new anti–TB drugs. <b>Methods:</b> Methods of nonparametric statistics were used to analyze the DST results and medico-social features of 84 patients of Ural Research Institute with MDR/XDR TB in 2020. DST was performed for M. tuberculosis isolates to the first, second line anti–TB drugs and LNZ on MGIT960 system with critical concentration as recommended by WHO. There were examined sputum and lung surgical material respectively in 49 (58,3%) and 15 (17,9%) patients with pulmonary TB, surgical bone material in 20 (23,8%) patients with TB spondylitis. <b>Results:</b> MDR was identified in 5 (6,0%) patients, pre-XDR - in 40 (47,6%), XDR - in 39 (46,4%). In pre- and XDR patients were identified the resistance to Mfx in 53 persons (63,1%), in 4 (4,85%) - to BDQ, in 6 (7,2%) - to LNZ. Among them TB duration up to three years or more was observed in 31 (58,5%) patients, contact with MDR/XDR TB in 27 (50,9%), HIV infection in 22 (41,5%), low treatment compliance in 27 (50,95%) and 14 (26,4%) patients interrupted courses, including BDQ, LNZ, Mfx. <b>Measurements and Main Results:</b> TB duration up to three years or more, сontact with MDR/XDR TB, coinfection HIV/TB, low treatment compliance and interrupted courses are combined primarily with the Mfx resistance, may be considered as the risk factors and require DST. Low percentage of BDQ and LNZ resistance make their widespread use in MDR/XDR TB regimen reasonable.
Unilateral beard
Authors: Jingru Sun, Yang Wang
Journal: BMJ (2022)

We initiated a double-blind, placebo-controlled trial to test the efficacy and safety of branched-chain amino acids (BCAA) (L-leucine 12 g, L-isoleucine 6 g, and L-valine 6 g daily) in amyotrophic lateral sclerosis (ALS) patients. There was an excess mortality in subjects randomized to active treatment (24 BCAA, 13 placebo) when a total of 126 ALS patients had been recruited. This finding, associated with the lack of efficacy of BCAA (measured by comparing the disability scales in the two treatment groups), led the Data Monitoring Committee to require cessation of the trial.
Width of excision margins after breast conserving surgery for invasive breast cancer and distant recurrence and survival
Authors: N J Bundred, J R Bundred, R I Cutress, D Dodwell
Journal: BMJ (2022)

One premise of cancer treatment is that if a tumour is cut out but tumour cells remain present or close to the edges (of the cut), the risk of cancer returning at the same site is increased. Increased surgical focus on adequacy of margin excision would improve breast cancer survival worldwide.
Culture of surgery must change to support working parents, says royal college
Authors: Gareth Iacobucci
Journal: BMJ (2022)

<h3>Background</h3> Several factors have been reported that influence the probability of a germline <i>CDKN2A</i> mutation in a melanoma family. Our goal was to create a scoring system to estimate this probability, based on a set of clinical features present in the patient and his or her family. <h3>Methods</h3> Five clinical features and their association with <i>CDKN2A</i> mutations were investigated in a training cohort of 1227 Dutch melanoma families (13.7% with <i>CDKN2A</i> mutation) using multivariate logistic regression. Predefined features included number of family members with melanoma and with multiple primary melanomas, median age at diagnosis and presence of pancreatic cancer or upper airway cancer in a family member. Based on these five features, a scoring system (<i>CDKN2A Mutation</i>(<i>CM</i>)<i>-Score</i>) was developed and subsequently validated in a combined Swedish and Dutch familial melanoma cohort (n=421 families; 9.0% with <i>CDKN2A</i> mutation). <h3>Results</h3> All five features were significantly associated (p&lt;0.05) with a <i>CDKN2A</i> mutation. At a CM-Score of 16 out of 49 possible points, the threshold of 10% mutation probability is approximated (9.9%; 95% CI 9.8 to 10.1). This probability further increased to &gt;90% for families with ≥36 points. A CM-Score under 16 points was associated with a low mutation probability (≤4%). CM-Score performed well in both the training cohort (area under the curve (AUC) 0.89; 95% CI 0.86 to 0.92) and the external validation cohort (AUC 0.94; 95% CI 0.90 to 0.98). <h3>Conclusion</h3> We developed a practical scoring system to predict <i>CDKN2A</i> mutation status among melanoma-prone families. We suggest that <i>CDKN2A</i> analysis should be recommended to families with a CM-Score of ≥16 points.
Inverted direct allorecognition triggers early donor-specific antibody responses after transplantation
Authors: Xavier Charmetant, Chien-Chia Chen, Sarah Hamada, David Goncalves, Carole Saison, Maud Rabeyrin, Marion Rabant, Jean-Paul Duong van Huyen, Alice Koenig, Virginie Mathias, Thomas Barba, Florence Lacaille, Jérôme le Pavec, Olivier Brugière, Jean-Luc Taupin, Lara Chalabreysse, Jean-François Mornex, Lionel Couzi, Stéphanie Graff-Dubois, Raphaël Jeger-Madiot, Alexy Tran-Dinh, Pierre Mordant, Helena Paidassi, Thierry Defrance, Emmanuel Morelon, Lionel Badet, Antonino Nicoletti, Valérie Dubois, Olivier Thaunat
Journal: Science Translational Medicine (2022)

The generation of antibodies against donor-specific major histocompatibility complex (MHC) antigens, a type of donor-specific antibodies (DSAs), after transplantation requires that recipient's allospecific B cells receive help from T cells. The current dogma holds that this help is exclusively provided by the recipient's CD4+ T cells that recognize complexes of recipient's MHC II molecules and peptides derived from donor-specific MHC alloantigens, a process called indirect allorecognition. Here, we demonstrated that, after allogeneic heart transplantation, CD3ε knockout recipient mice lacking T cells generate a rapid, transient wave of switched alloantibodies, predominantly directed against MHC I molecules. This is due to the presence of donor CD4+ T cells within the graft that recognize intact recipient's MHC II molecules expressed by B cell receptor-activated allospecific B cells. Indirect evidence suggests that this inverted direct pathway is also operant in patients after transplantation. Resident memory donor CD4+ T cells were observed in perfusion liquids of human renal and lung grafts and acquired B cell helper functions upon in vitro stimulation. Furthermore, T follicular helper cells, specialized in helping B cells, were abundant in mucosa-associated lymphoid tissue of lung and intestinal grafts. In the latter, more graft-derived passenger T cells correlated with the detection of donor T cells in recipient's circulation; this, in turn, was associated with an early transient anti-MHC I DSA response and worse transplantation outcomes. We conclude that this inverted direct allorecognition is a possible explanation for the early transient anti-MHC DSA responses frequently observed after lung or intestinal transplantations.
A Single-Arm Phase Ib/II Study of Lenvatinib plus Eribulin in Advanced Liposarcoma and Leiomyosarcoma
Authors: Tom Wei-Wu Chen, Chia-Lang Hsu, Ruey-Long Hong, Jen-Chieh Lee, Koping Chang, Chih-Wei Yu, San-Chi Chen, Jhe-Cyuan Guo, Mei-Lu Chen, Meng-Chi Hsu, Ting-Fang Kung, Ann-Lii Cheng, Chueh-Chuan Yen
Journal: Clinical Cancer Research (2022)

Satisfactory treatment options for advanced leiomyosarcoma and liposarcoma are limited. The LEADER study (NCT03526679) investigated the safety and efficacy of lenvatinib plus eribulin.LEADER is a multicenter phase Ib/II study for advanced leiomyosarcoma or liposarcoma. The phase Ib part enrolled 6 patients to determine the dose-limiting toxicity (DLT) and recommended phase II dose (RP2D) with the starting dose of lenvatinib 18 mg/day and eribulin 1.1 mg/m2 D1, D8 every 21 days. The primary endpoint of the phase II part was objective response rate (ORR) based on Response Evaluation Criteria in Solid Tumors 1.1, with phase Ib patients preplanned to be included in the efficacy analysis. Translational analyses were based on the transcriptomic data obtained from the NanoString nCounter platform.Thirty patients were enrolled (leiomyosarcoma 21, liposarcoma 9); the median age was 59. One patient had to temporarily stop lenvatinib due to grade 2 arthritis in the first cycle, meeting DLT criteria. Four of 6 patients had to decrease the dose of lenvatinib to 14 mg between cycles two and three. RP2D was determined at lenvatinib 14 mg/day and eribulin 1.1 mg/m2. The confirmed ORR was 20%, and the ORR was not significantly different between phase Ib/II cohorts (P = 0.23). The median progression-free survival was 8.56 months (95% confidence interval, 4.40-not reached). Translational studies suggested increased dendritic cells in the tumor microenvironment (TME) after treatment.Lenvatinib plus eribulin has a manageable safety profile and exhibits promising efficacy for treating advanced leiomyosarcoma and liposarcoma.
CD8+ Tumor-Infiltrating Lymphocyte Abundance Is a Positive Prognostic Indicator in Nasopharyngeal Cancer
Authors: Wei Shi, Mackenzie Fijardo, Jeff P. Bruce, Jie Su, Wei Xu, Rachel Bell, Pierre-Antoine Bissey, Angela B.Y. Hui, John Waldron, Trevor J. Pugh, Kenneth W. Yip, Fei-Fei Liu
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Tumor-infiltrating lymphocytes (TIL) are immune cell populations found within tumors, critical in the antigen-specific host immune response. In this study, we aimed to elucidate the prognostic significance of CD3+, CD4+, and CD8+ TILs in nasopharyngeal cancer (NPC). Experimental Design: Immune cell infiltration was quantified in NPC samples (n = 50) using RNA-sequencing (RNA-seq) data based on rearranged T-cell receptor (TCR) reads and the Estimation of Stromal and Immune cells in malignant tumors using expression data (ESTIMATE) immune score tool. The differential abundances of TIL subset populations were also characterized through IHC staining of formalin-fixed, paraffin-embedded samples from a training cohort (n = 35), which was a subset of the RNA-seq cohort (n = 50). Results: In the RNA-seq cohort, patients with higher rearranged TCR reads experienced superior 5- and 10-year overall survival (OS; P &amp;lt; 0.001), and disease-free survival (DFS; P &amp;lt; 0.001). Similarly, patients with higher ESTIMATE immune scores experienced superior 5- and 10-year OS (P = 0.024) and DFS (P = 0.007). In the training cohort, high abundances of CD8+ TILs were significantly associated with improved 5- and 10-year OS (P = 0.003) and DFS (P = 0.005). These findings were corroborated in an independent validation cohort (n = 84), and combined analysis of the training and validation cohorts [n = 119 (35+84)], which further demonstrated improved 5- and 10-year survival in terms of locoregional control (P &amp;lt; 0.001) and distant metastasis (P = 0.03). Conclusions: Taken together, our study highlights the prognostic value of CD8+ TILs in NPC, and the potential of future investigations into cellular-based immunotherapies employing CD8+ lymphocytes.
A Therapeutic Antigen-Presenting Cell-Targeting DNA Vaccine VB10.16 in HPV16-Positive High-Grade Cervical Intraepithelial Neoplasia: Results from a Phase I/IIa Trial
Authors: Peter Hillemanns, Agnieszka Denecke, Linn Woelber, Gerd Böhmer, Matthias Jentschke, Karoline W. Schjetne, Karsten M.H. Bruins Slot, Agnete B. Fredriksen
Journal: Clinical Cancer Research (2022)

Abstract Purpose: To evaluate the safety, immunogenicity and efficacy of a therapeutic DNA vaccine VB10.16, using a unique modular vaccine technology that is based on linking antigens to CCL3L1 targeting module, in women with HPV16-positive high-grade cervical intraepithelial neoplasia (CIN). Patients and Methods: We conducted a first-in-human, open-label, phase I/IIa clinical trial of VB10.16 in subjects with confirmed HPV16-positive CIN 2/3. The primary endpoint was the proportion of participants with adverse events, including dose-limiting toxicities. Secondary outcome measures included measuring the E6/E7-specific cellular immune response. In the Expansion cohort HPV16 clearance, regression of CIN lesion size and grading were assessed during a 12-month follow-up period. Results: A total of 34 women were enrolled: 16 in two dose cohorts and 18 in the expansion cohort. No serious adverse events or dose-limiting toxicities were observed, and none of the subjects discontinued treatment with VB10.16 due to an adverse event. Mild to moderate injection site reactions were the most commonly reported adverse event (79%). HPV16-specific T-cell responses were observed after vaccination in the majority of the subjects. In the expansion cohort, HPV16 clearance was seen in 8 of 17 evaluable subjects (47%). Reductions in lesion size were seen in 16 subjects (94%) and 10 subjects (59%) had regression to CIN 0/1. Correlation between strong IFNγ T-cell responses and lesion size reduction was statistically significant (P &amp;lt; 0.001) Conclusions: The novel therapeutic DNA vaccine VB10.16 was well tolerated and showed promising evidence of efficacy and strong HPV16-specific T-cell responses in subjects with high-grade CIN.
Molecular Monitoring of Lymphomas
Authors: Joseph G. Schroers-Martin, Stefan Alig, Andrea Garofalo, Benoit Tessoulin, Takeshi Sugio, Ash A. Alizadeh
Journal: Annual Review of Pathology Mechanisms of Disease (2022)

Molecular monitoring of tumor-derived alterations has an established role in the surveillance of leukemias, and emerging nucleic acid sequencing technologies are likely to similarly transform the clinical management of lymphomas. Lymphomas are well suited for molecular surveillance due to relatively high cell-free DNA and circulating tumor DNA concentrations, high somatic mutational burden, and the existence of stereotyped variants enabling focused interrogation of recurrently altered regions. Here, we review the clinical scenarios and key technologies applicable for the molecular monitoring of lymphomas, summarizing current evidence in the literature regarding molecular subtyping and classification, evaluation of treatment response, the surveillance of active cellular therapies, and emerging clinical trial strategies.
Post-submission changes to prespecified statistical analysis plans
Authors: Nazrul Islam, Tim J Cole, Joseph S Ross, Timothy Feeney, Elizabeth Loder
Journal: BMJ (2022)

Transparency and reproducibility are two of the fundamental principles of evidence generation and dissemination of research knowledge. 1 2Researchers ask questions, challenge answers, replicate results, and scrutinise findings-this is how we accumulate knowledge and help develop evidence based policy.Scientific integrity, reliability, reproducibility, and transparency are paramount if scientific studies are to serve as the basis for policies that can have a big effect on human wellbeing. 3 Detailed guidelines on writing a prespecified research protocol and statistical analysis plan have been developed to improve the transparency and reproducibility of research. 4 -6Prespecified plans have a critical role in minimising and detecting selective analysis and reporting. 7 8The BMJ requires authors of clinical trials to upload their protocol and statistical analysis plans during submission, and encourages it for other study types.The protocols and analysis plans of all accepted studies are published alongside their findings. 9This is to reassure readers that the analysis was honest, did not involve post-hoc preferential analysis or selective reporting of favourable results, and that no additional analysis was done before publication to bias the findings.
Distinct Cell Adhesion Signature Defines Glioblastoma Myeloid-Derived Suppressor Cell Subsets
Authors: Defne Bayik, Cynthia F. Bartels, Katreya Lovrenert, Dionysios C. Watson, Duo Zhang, Kristen Kay, Juyeun Lee, Adam Lauko, Sadie Johnson, Alice Lo, Daniel J. Silver, Mary McGraw, Matthew Grabowski, Alireza M. Mohammadi, Filippo Veglia, Yi Fan, Michael A. Vogelbaum, Peter Scacheri, Justin D. Lathia
Journal: Cancer Research (2022)

Abstract In multiple types of cancer, an increased frequency in myeloid-derived suppressor cells (MDSC) is associated with worse outcomes and poor therapeutic response. In the glioblastoma (GBM) microenvironment, monocytic (m) MDSCs represent the predominant subset. However, the molecular basis of mMDSC enrichment in the tumor microenvironment compared with granulocytic (g) MDSCs has yet to be determined. Here we performed the first broad epigenetic profiling of MDSC subsets to define underlying cell-intrinsic differences in behavior and found that enhanced gene accessibility of cell adhesion programs in mMDSCs is linked to their tumor-accelerating ability in GBM models upon adoptive transfer. Mouse and human mMDSCs expressed higher levels of integrin β1 and dipeptidyl peptidase-4 (DPP-4) compared with gMDSCs as part of an enhanced cell adhesion signature. Integrin β1 blockade abrogated the tumor-promoting phenotype of mMDSCs and altered the immune profile in the tumor microenvironment, whereas treatment with a DPP-4 inhibitor extended survival in preclinical GBM models. Targeting DPP-4 in mMDSCs reduced pERK signaling and their migration towards tumor cells. These findings uncover a fundamental difference in the molecular basis of MDSC subsets and suggest that integrin β1 and DPP-4 represent putative immunotherapy targets to attenuate myeloid cell-driven immune suppression in GBM. Significance: Epigenetic profiling uncovers cell adhesion programming as a regulator of the tumor-promoting functions of monocytic myeloid-derived suppressor cells in glioblastoma, identifying therapeutic targets that modulate the immune response and suppress tumor growth.
Genomics and epigenetics guided identification of tissue-specific genomic safe harbors
Authors: Dewan Shrestha, Aishee Bag, Ruiqiong Wu, Yeting Zhang, Xing Tang, Qian Qi, Jinchuan Xing, Yong Cheng
Journal: Genome biology (2022)

Genomic safe harbors are regions of the genome that can maintain transgene expression without disrupting the function of host cells. Genomic safe harbors play an increasingly important role in improving the efficiency and safety of genome engineering. However, limited safe harbors have been identified.
Crafted responses to covid belong in national galleries
Authors: John Puntis
Journal: BMJ (2022)

Chronic airway diseases including asthma and COPD are prevalent and high-burden conditions with the majority of patients successfully managed in the primary care setting. However, for some patients with more complex disease such as difficult-to-treat or severe asthma, or complex COPD, tertiary care is required. This review provides an overview of the successful tertiary care multidisciplinary respiratory service that operates in Newcastle, New South Wales, Australia, which has been integrated into the tertiary care outpatient clinics for almost three decades. The service is multifaceted in terms of the clinical care it provides; it includes an “Inpatient Service”, “Asthma Management Service”, “Difficult Airways Clinic”, “Drug Administration Clinic”, “Rapid Access Clinic” and “Pulmonary Rehabilitation”, and has an integrated research programme. The core of the multidisciplinary approach to airway diseases is a person-centred model of care, the “Treatable Traits” approach. The staffing of this service comprises consultant physicians, respiratory advanced trainees, respiratory scientists, physiotherapists, speech pathologists, nurse specialists and a nurse consultant. Patients that present to this service undergo an initial assessment and clinical review by team members, synthesis of relevant data, and development of a diagnosis and management plan. Based on this clinical review, specific interventions are determined according to the traits identified. Over time the service has evolved to accommodate the increasing numbers of patients requiring access to the Difficult Airways Clinic assessment and therapies. This has been facilitated by partnering with the Centres of Excellence in Severe Asthma and Treatable Traits to develop educational and practice management tools.
Genomic profiling for clinical decision making in myeloid neoplasms and acute leukemia
Authors: Eric J. Duncavage, Adam Bagg, Robert P. Hasserjian, Courtney D. DiNardo, Lucy A. Godley, Ilaria Iacobucci, Siddhartha Jaiswal, Luca Malcovati, Alessandro M. Vannucchi, Keyur P. Patel, Daniel A. Arber, Maria E. Arcila, Rafael Bejar, Nancy Berliner, Michael J. Borowitz, Susan Branford, Anna L. Brown, Catherine A. Cargo, Hartmut Döhner, Brunangelo Falini, Guillermo Garcia-Manero, Torsten Haferlach, Eva Hellström-Lindberg, Annette S. Kim, Jeffery M. Klco, Rami Komrokji, Mignon Lee-Cheun Loh, Sanam Loghavi, Charles G. Mullighan, Seishi Ogawa, Attilio Orazi, Elli Papaemmanuil, Andreas Reiter, David M. Ross, Michael Savona, Akiko Shimamura, Radek C. Skoda, Francesc Solé, Richard M. Stone, Ayalew Tefferi, Matthew J. Walter, David Wu, Benjamin L. Ebert, Mario Cazzola
Journal: Blood (2022)
Giredestrant reverses progesterone hypersensitivity driven by estrogen receptor mutations in breast cancer
Authors: Jackson Liang, Ellen Rei Ingalla, Xiaosai Yao, Bu-Er Wang, Lisa Tai, Jennifer Giltnane, Yuxin Liang, Anneleen Daemen, Heather M. Moore, Junko Aimi, Ching-Wei Chang, Mary R. Gates, Jennifer Eng-Wong, Lucinda Tam, Natasha Bacarro, Merone Roose-Girma, Meritxell Bellet, Marc Hafner, Ciara Metcalfe
Journal: Science Translational Medicine (2022)

ESR1 (estrogen receptor 1) hotspot mutations are major contributors to therapeutic resistance in estrogen receptor-positive (ER+) breast cancer. Such mutations confer estrogen independence to ERα, providing a selective advantage in the presence of estrogen-depleting aromatase inhibitors. In addition, ESR1 mutations reduce the potency of tamoxifen and fulvestrant, therapies that bind ERα directly. These limitations, together with additional liabilities, inspired the development of the next generation of ERα-targeted therapeutics, of which giredestrant is a high-potential candidate. Here, we generated Esr1 mutant-expressing mammary gland models and leveraged patient-derived xenografts (PDXs) to investigate the biological properties of the ESR1 mutations and their sensitivity to giredestrant in vivo. In the mouse mammary gland, Esr1 mutations promote hypersensitivity to progesterone, triggering pregnancy-like tissue remodeling and profoundly elevated proliferation. These effects were driven by an altered progesterone transcriptional response and underpinned by gained sites of ERα-PR (progesterone receptor) cobinding at the promoter regions of pro-proliferation genes. PDX experiments showed that the mutant ERα-PR proliferative program is also relevant in human cancer cells. Giredestrant suppressed the mutant ERα-PR proliferation in the mammary gland more so than the standard-of-care agents, tamoxifen and fulvestrant. Giredestrant was also efficacious against the progesterone-stimulated growth of ESR1 mutant PDX models. In addition, giredestrant demonstrated activity against a molecularly characterized ESR1 mutant tumor from a patient enrolled in a phase 1 clinical trial. Together, these data suggest that mutant ERα can collaborate with PR to drive protumorigenic proliferation but remain sensitive to inhibition by giredestrant.